HIF-1alpha contributes to tumour-selective killing by the sigma receptor antagonist rimcazole

M Achison, M T Boylan, T R Hupp, B A Spruce

Research output: Contribution to journalArticlepeer-review

Abstract

We have previously reported tumour-selective killing by the sigma (sigma) receptor ligand rimcazole. We now report that rimcazole elevates hypoxia inducible factor-1alpha (HIF-1alpha) protein levels under normoxic conditions in colorectal (HCT-116) and mammary carcinoma (MDA MB 231) cells but fails to induce HIF-1alpha in normal fibroblasts or mammary epithelial cells. Combining the sigma-1 agonist (+)-pentazocine with rimcazole substantially reduces the accumulation of HIF-1alpha, confirming that the effect is mediated at least partly by antagonism of sigma-1 sites. HIF-1alpha knockdown by RNA interference attenuates rimcazole-induced cell death in both cell types. Thus, the induction of HIF-1alpha by rimcazole contributes to tumour cell killing. In a comparison of HCT-116p53+/+ and HCT-116p53-/- cells, HIF-1alpha levels are consistently higher after rimcazole treatment in HCT-116p53+/+ cells. Furthermore, although rimcazole kills HCT-116p53-/- cells, it has a more potent apoptosis-inducing effect in HCT-116p53+/+ cells. This suggests that the presence of functional p53 protein may enhance death induction by rimcazole in part through greater induction of HIF-1alpha. p53 is not required, however, for the rimcazole-induced engagement of HIF-1alpha in proapoptotic mode as HIF-1alpha knockdown attenuates rimcazole-induced death to comparable extents in p53 mutant and wild-type cell systems. Knowledge of HIF-1alpha involvement may assist the re-profiling of rimcazole and other sigma ligands as cancer therapeutics.
Original languageEnglish
Pages (from-to)1137-46
Number of pages10
JournalOncogene
Volume26
Issue number8
DOIs
Publication statusPublished - 22 Feb 2007

Keywords

  • Apoptosis
  • Carbazoles
  • Cell Line, Tumor
  • Epithelial Cells
  • Fibroblasts
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Neoplasms
  • Pentazocine
  • RNA Interference
  • Receptors, sigma
  • Tumor Suppressor Protein p53
  • Up-Regulation

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